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Article: Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease.

Borza, Corina M / Bolas, Gema / Pozzi, Ambra

2022 Volume 13, Page(s) 1001122

Abstract: Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of ...

Abstract	Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisense-based inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis.
Language	English
Publishing date	2022-09-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.1001122
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Discoidin Domain Receptor 2, a Potential Therapeutic Target in Lung Fibrosis.

Borza, Corina M / Pozzi, Ambra / Plosa, Erin J

American journal of respiratory cell and molecular biology

2018 Volume 59, Issue 3, Page(s) 277–278

MeSH term(s)	Apoptosis ; Discoidin Domain Receptor 2 ; Fibroblasts ; Proto-Oncogene Proteins c-akt ; Signal Transduction
Chemical Substances	Discoidin Domain Receptor 2 (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2018-07-18
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2018-0161ED
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Article ; Online: Discoidin domain receptors in disease.

Borza, Corina M / Pozzi, Ambra

Matrix biology : journal of the International Society for Matrix Biology

2013 Volume 34, Page(s) 185–192

Abstract: Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to ...

Abstract	Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling. While activation of DDRs by extracellular matrix collagens is required for normal development and tissue homeostasis, aberrant activation of these receptors following injury or in disease is detrimental. The availability of mice lacking DDRs has enabled us to identify key roles played by these receptors in disease initiation and progression. DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury, while DDR2 contributes to osteoarthritis. Furthermore, both DDRs have been implicated in cancer progression. Yet the mechanisms whereby DDRs contribute to disease progression are poorly understood. In this review we highlight the mechanisms whereby DDRs regulate two important processes, namely inflammation and tissue fibrosis. In addition, we discuss the challenges of targeting DDRs in disease. Selective targeting of these receptors requires understanding of how they interact with and are activated by extracellular matrix, and whether their cellular function is dependent on or independent of receptor kinase activity.
MeSH term(s)	Animals ; Cell Movement/genetics ; Cell Proliferation ; Discoidin Domain Receptor 1 ; Discoidin Domain Receptors ; Extracellular Matrix/genetics ; Extracellular Matrix/pathology ; Fibrosis/genetics ; Fibrosis/pathology ; Humans ; Inflammation/genetics ; Inflammation/pathology ; Mice ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, Mitogen/genetics ; Receptors, Mitogen/metabolism ; Signal Transduction/genetics
Chemical Substances	Receptors, Mitogen ; DDR1 protein, human (EC 2.7.10.1) ; Discoidin Domain Receptor 1 (EC 2.7.10.1) ; Discoidin Domain Receptors (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2013-12-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2013.12.002
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Zs.A 1694: Show issues

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Article: Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy.

Jeffries, Daniel E / Borza, Corina M / Blobaum, Anna L / Pozzi, Ambra / Lindsley, Craig W

ACS medicinal chemistry letters

2019 Volume 11, Issue 1, Page(s) 29–33

Abstract: Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor, ...

Abstract	Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor,
Language	English
Publishing date	2019-11-25
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.9b00382
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Article ; Online: The role of cell-extracellular matrix interactions in glomerular injury.

Borza, Corina M / Pozzi, Ambra

Experimental cell research

2012 Volume 318, Issue 9, Page(s) 1001–1010

Abstract: Glomerulosclerosis is characterized by excessive deposition of extracellular matrix within the glomeruli of the kidney, glomerular cell death, and subsequent loss of functional glomeruli. While in physiological situations the levels of extracellular ... ...

Abstract	Glomerulosclerosis is characterized by excessive deposition of extracellular matrix within the glomeruli of the kidney, glomerular cell death, and subsequent loss of functional glomeruli. While in physiological situations the levels of extracellular matrix components are kept constant by a tight balance between formation and degradation, in the case of injury that results in fibrosis there is increased matrix deposition relative to its breakdown. Multiple factors control matrix synthesis and degradation, thus contributing to the development of glomerulosclerosis. This review focuses primarily on the role of cell-matrix interactions, which play a critical role in governing glomerular cell cues in both healthy and diseased kidneys. Cell-extracellular matrix interactions are made possible by various cellular receptors including integrins, discoidin domain receptors, and dystroglycan. Upon binding to a selective extracellular matrix protein, these receptors activate intracellular signaling pathways that can either downregulate or upregulate matrix synthesis and deposition. This, together with the observation that changes in the expression levels of matrix receptors have been documented in glomerular disease, clearly emphasizes the contribution of cell-matrix interactions in glomerular injury. Understanding the molecular mechanisms whereby extracellular matrix receptors regulate matrix homeostasis in the course of glomerular injury is therefore critical for devising more effective therapies to treat and ideally prevent glomerulosclerosis.
MeSH term(s)	Animals ; Extracellular Matrix/metabolism ; Glomerulonephritis/metabolism ; Glomerulonephritis/pathology ; Humans ; Integrins/metabolism ; Kidney/metabolism ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology
Chemical Substances	Integrins
Language	English
Publishing date	2012-03-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.02.033
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Zs.A 563: Show issues

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Article: The role of cell–extracellular matrix interactions in glomerular injury

Borza, Corina M / Pozzi, Ambra

Experimental cell research. 2012 May 15, v. 318, no. 9

2012

Abstract	Glomerulosclerosis is characterized by excessive deposition of extracellular matrix within the glomeruli of the kidney, glomerular cell death, and subsequent loss of functional glomeruli. While in physiological situations the levels of extracellular matrix components are kept constant by a tight balance between formation and degradation, in the case of injury that results in fibrosis there is increased matrix deposition relative to its breakdown. Multiple factors control matrix synthesis and degradation, thus contributing to the development of glomerulosclerosis. This review focuses primarily on the role of cell–matrix interactions, which play a critical role in governing glomerular cell cues in both healthy and diseased kidneys. Cell–extracellular matrix interactions are made possible by various cellular receptors including integrins, discoidin domain receptors, and dystroglycan. Upon binding to a selective extracellular matrix protein, these receptors activate intracellular signaling pathways that can either downregulate or upregulate matrix synthesis and deposition. This, together with the observation that changes in the expression levels of matrix receptors have been documented in glomerular disease, clearly emphasizes the contribution of cell–matrix interactions in glomerular injury. Understanding the molecular mechanisms whereby extracellular matrix receptors regulate matrix homeostasis in the course of glomerular injury is therefore critical for devising more effective therapies to treat and ideally prevent glomerulosclerosis.
Keywords	cell death ; extracellular matrix ; fibrosis ; homeostasis ; integrins ; kidney glomerulus ; receptors ; signal transduction
Language	English
Dates of publication	2012-0515
Size	p. 1001-1010.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.02.033
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Article ; Online: DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3.

Borza, Corina M / Bolas, Gema / Bock, Fabian / Zhang, Xiuqi / Akabogu, Favour C / Zhang, Ming-Zhi / de Caestecker, Mark / Yang, Min / Yang, Haichun / Lee, Ethan / Gewin, Leslie / Fogo, Agnes B / McDonald, W Hayes / Zent, Roy / Pozzi, Ambra

JCI insight

2022 Volume 7, Issue 3

Abstract: Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model ... ...

Abstract	Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal tubule epithelial cells. DDR1-induced BCR phosphorylation or BCR downregulation increased MCP-1 secretion, suggesting that BCR negatively regulates the levels of MCP-1. Mechanistically, phosphorylation or downregulation of BCR increased β-catenin activity and in turn MCP-1 production. Finally, we showed that DDR1-mediated STAT3 activation was required to stimulate the secretion of TGF-β. Thus, DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-β. These findings identify DDR1 an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease.
MeSH term(s)	Acute Kidney Injury ; Animals ; Cell Line ; Cells, Cultured ; Discoidin Domain Receptor 1/biosynthesis ; Discoidin Domain Receptor 1/genetics ; Female ; Fibrosis/complications ; Fibrosis/genetics ; Fibrosis/pathology ; Gene Expression Regulation ; Inflammation/complications ; Inflammation/genetics ; Inflammation/pathology ; Kidney Tubules, Proximal/metabolism ; Kidney Tubules, Proximal/pathology ; Male ; Mice ; Mice, Knockout ; Phosphorylation ; Proto-Oncogene Proteins c-bcr/biosynthesis ; Proto-Oncogene Proteins c-bcr/genetics ; RNA/genetics ; STAT3 Transcription Factor/biosynthesis ; STAT3 Transcription Factor/genetics ; Signal Transduction
Chemical Substances	STAT3 Transcription Factor ; Stat3 protein, mouse ; RNA (63231-63-0) ; Ddr1 protein, mouse (EC 2.7.10.1) ; Discoidin Domain Receptor 1 (EC 2.7.10.1) ; Bcr protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins c-bcr (EC 2.7.11.1)
Language	English
Publishing date	2022-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.150887
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Article: Cell Receptor-Basement Membrane Interactions in Health and Disease: A Kidney-Centric View.

Borza, Corina M / Chen, Xiwu / Zent, Roy / Pozzi, Ambra

Current topics in membranes

2015 Volume 76, Page(s) 231–253

Abstract: Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with ... ...

Abstract	Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with cells via cellular receptors, including integrins and discoidin domain receptors. Disruption of cell-BM interactions due to either injury or genetic defects in either the ECM components or cellular receptors often lead to irreversible tissue injury and loss of organ function. Animal models that lack specific BM components or receptors either globally or in selective tissues have been used to help with our understanding of the molecular mechanisms whereby cell-BM interactions regulate organ function in physiological and pathological conditions. We review recently published works on animal models that explore how cell-BM interactions regulate kidney homeostasis in both health and disease.
MeSH term(s)	Animals ; Basement Membrane/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Humans ; Kidney/cytology ; Kidney/metabolism ; Kidney/pathology ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Protein Binding ; Receptors, Cell Surface/metabolism
Chemical Substances	Receptors, Cell Surface
Language	English
Publishing date	2015-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ISSN	1063-5823
ISSN	1063-5823
DOI	10.1016/bs.ctm.2015.07.003
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Article: The Collagen Receptor Discoidin Domain Receptor 1b Enhances Integrin β1-Mediated Cell Migration by Interacting With Talin and Promoting Rac1 Activation.

Borza, Corina M / Bolas, Gema / Zhang, Xiuqi / Browning Monroe, Mary Beth / Zhang, Ming-Zhi / Meiler, Jens / Skwark, Marcin J / Harris, Raymond C / Lapierre, Lynne A / Goldenring, James R / Hook, Magnus / Rivera, Jose / Brown, Kyle L / Leitinger, Birgit / Tyska, Matthew J / Moser, Markus / Böttcher, Ralph T / Zent, Roy / Pozzi, Ambra

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 836797

Abstract: Integrins and discoidin domain receptors (DDRs) 1 and 2 promote cell adhesion and migration on both fibrillar and non fibrillar collagens. Collagen I contains DDR and integrin selective binding motifs; however, the relative contribution of these two ... ...

Abstract	Integrins and discoidin domain receptors (DDRs) 1 and 2 promote cell adhesion and migration on both fibrillar and non fibrillar collagens. Collagen I contains DDR and integrin selective binding motifs; however, the relative contribution of these two receptors in regulating cell migration is unclear. DDR1 has five isoforms (DDR1a-e), with most cells expressing the DDR1a and DDR1b isoforms. We show that human embryonic kidney 293 cells expressing DDR1b migrate more than DDR1a expressing cells on DDR selective substrata as well as on collagen I
Language	English
Publishing date	2022-03-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.836797
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Article ; Online: Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.

Kothiwale, Sandeepkumar / Borza, Corina M / Lowe, Edward W / Pozzi, Ambra / Meiler, Jens

Drug discovery today

2014 Volume 20, Issue 2, Page(s) 255–261

Abstract: Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, ... ...

Abstract	Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable.
MeSH term(s)	Animals ; Discoidin Domain Receptors ; Drug Discovery ; Humans ; Molecular Structure ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Tertiary ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/chemistry ; Receptors, Mitogen/antagonists & inhibitors ; Receptors, Mitogen/chemistry
Chemical Substances	Protein Kinase Inhibitors ; Receptors, Mitogen ; Discoidin Domain Receptors (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2014-10-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2014.09.025
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